1. Field of the Invention
This invention relates to novel fluorinated phenyl thiphenyl (also named diarylsulfide) derivatives and their use in Positron Emission Tomagraphy (PET) imaging of Serotonin Transporters.
2. Related Art
Depression, with its related conditions, is one of the most common mental disorders in the United States. It is estimated that about five percent of the adult population experiences a depressive episode in their lifetime that requires antidepressive drug therapy. A chemical in the human brain, called serotonin, has been linked with depression and with other psychiatric disorders such as eating disorders, alcoholism, pain, anxiety and obsessive-compulsive behavior.
Abnormalities in the serotonin transporter (SERT) have been implicated in several neurologic and psychiatric disorders, such as Parkinsonian disorder, depression, suicide, schizophrenia, drug addiction and eating disorders (Mann et al. 2000; Meltzer et al. 1998). In addition, SERT is the primary target for the widely prescribed antidepressant agent (Frazer, 1997). In order to study the above mentioned neurologic and psychiatric disorders, and the mode of action of antidepressant agents in humans, it is of great need to have high affinity and high specificity SERT radioligands for both SPECT and PET studies.
Serotonin (5-HT) is an essential neurotransmitter for the normal function of the central nervous system. This neurotransmission system in the brain controls various important behaviors, including sleep awake cycle, mood, temperature, appetite, etc. In addition, several commonly used anti-anxienty anxiety drugs (Frazer, A. and J. G. Hensler, Ann. NY Acad. Sci. 600:460-475 (1990); Gozlan, H. and M. Hamon, Anxiety: Neurobiol., Clinic and Ther. Persp. 232:141-150 (1993)) and antidepressants (Frazer, A., J. Clin. Psychiatry 6:9-25 (1997); Coryell, W., J Clin. Psychiatry 1:22-27 (1998); Heninger, G. R. et al., Pharmacopsychiatry 29(1):2-11 (1996); Fuller, R. W., Prog. Drug Res. 45:167-204 (1995)) interact specifically with serotonin neurotransmission. Pharmacological actions of the antidepressants (selective serotonin reuptake inhibitors; SSRI), such as fluoxetine (Wong, D. T. and F. P. Byrnaster, Biology 363:77-95 (1995)), paroxetine (Holliday, S. M. and G. L. Plosker, Drugs Aging 3(3)278-299 (1993)) and sertraline (Lasne, M. C. et al., Int. J. Rad. Appl. Inst.—Part A, Applied Rad Isot. 40(2):147-151 (1989)), are based on blockade of presynaptic transporters for serotonin. Thus, studies of radioligand binding to serotonin transporter (SERT) may provide valuable information of these sites in normal and various disease states. Several tritiated ligands including imipramine (Raisman, R. et al., Eur. J. Pharmacol. 54:307-308 (1979)), citalopram (D'Amato, R. et al., Pharmacol. Exp. Ther. 242(1):364-371 (1987)), paroxetine (Habert, E., et al., Eur. J. Pharmacol. 118(1-2):107-114 (1985)) and 6-nitroquipazine (Hashimoto, K., and T. Goromaru, Biochem. Pharmacol. 41(11):1679-1682 (1991); Hashimoto K, and T. Goromaru, Neuropharmacology 30(2):113-117 (1991)) have been used for in vitro and in vivo studies. A reduced level of SERT labeled by these tritiated ligands has been demonstrated in post mortem brain sections of patients with depression (Perry, E. K. et al., Br. J. Psychiat. 142:188-192 (1983)), Alzheimer's and Parkinson's diseases (D'Amato, R. et al., Pharmacol Exp. Ther. 242(1):364-371 (1987)) as well as in the frontal cortex of a suicide victim (Mann, J. J., Nature Medicine 4(1):25-30 (1998)). The in vitro binding studies suggest that using in vivo imaging methods to evaluate the density of SERT may be clinically important.
Anti-depressive drugs, such as Prozac, operate to inhibit serotonin reuptake by binding with the serotonin transporter (SERT) protein, effectively blocking the binding of the protein with serotonin. Although Prozac has been found to be an effective anti-depressant treatment, it has side effects which can be serious. Prozac is known to bind to the serotonin transporter (SERT) protein, but the responses of patients can differ widely. Some patients experience greater binding than others. If a patient is not responding to Prozac treatment, there is currently no way to determine why that is the case. Frequently, the physician will simply administer greater doses of the drug, a practice which will not necessarily lead to better results and which can enhance undesirable side effects.
Development of selective tracers for positron emission tomography (PET) and single photon emission tomography (SPECT) have made it possible to study in vivo neuroreceptors or site-specific bindings non-invasively in the human brain. However, development of PET or SPECT tracers specifically for in vivo imaging of SERT has only met with limited success. The most promising radioligand described to date is [11C](+)McN5652 for PET imaging (Szabo, Z. et al., Synapse 20(1):37-43 (1995); Szabo, Z. et al., J. Nucl. Med. 37(5):125 (1996); Szabo, Z. Behav. Brain Res. 73(1):221-224 (1995); Szabo, Z. et al., J. Cerebral Blood Flow & Metabol. 15(5):798-805 (1995); Suehiro, M. et al., J. Nucl. Med. 34(1):120-127 (1993); Suehiro, M. et al., Nucl. Med. Biol. 22(4):543-545 (1995)). Specific binding of [11C](+)McN5652 correlates well with the known density of SERT sites in the human brain (Szabo, Z. et al., Synapse 20(1):37-43 (1995)).
Fluorine-18 has some advantages over carbon-11: 1). It has lower positron energy than carbon-11 (0.63 5 vs 0.96 MeV); 2). Because of the long half-life of fluorine 18, the PET studies can be performed for more than 2 hours if necessary; 3). The long half-life is convenient for radiosynthesis; and 4). The radioligands can be transported off site when a cyclotron is not available.
Several radioligands have been developed for PET studies of SERT. These include fluorine-18 labeled paroxetine (Suehiro et al., 1991), fluoxetine (Das and Mukherjee, 1993; Hammadi and Crouzel, 1993) and carbon-11 labeled cyanoimipramine (Hashimoto et al., 1987), citalopram (Hume et al., 1992), sertraline (Hume et al., 1989) and fluoxetine (Kilboum et al., 1989; Schaffel et al., 1990; Shiue et al., 1995). All of these radioligands were found not to be the ideal agents for PET studies of SERT due to their low specific-to-nonspecific binding ratios in vivo. For the last decade, [11C](+)McN 5652 (FIG. 1) has been the most promising PET agent for studying SERT in humans (Suehiro et al., 1993a,b). However, this agent has high nonspecific binding and has only moderate signal contrast in human PET studies (Szabo et al., 1995a,b; Buck et al., 2000; Parsey et al., 2000). Additionally, its pharmacokinetics is not optimal due to the short half-life of carbon-11. Labeling (+)McNeil 5652 with fluorine-18 did not improve its imaging properties (Suehiro et al., 1996; Zessin et al., 2001).